The primary mechanism by which chemical carcinogens induce the malignant transformation of mammalian cells is unknown. Four major theories for carcinogen action have been suggested: (1) Selection of pre-existing transformed cells; (2) Activation of viral oncogenic information; (3) Somatic mutation and (4) Epigenetic reprogramming of cellular differentiation. In this laboratory we are trying to obtain the kind of direct evidence that we feel is needed to determine the mechanism of action of chemical carcinogens. In one series of experiments, we are measuring the frequency of transformation and of reversion to normal by various transformed lines and obtaining evidence against the oncogenic theory of carcinogenesis. In another series of experiments, we are quantitatively studying the induction of conditionally transformed cells. This data is providing positive evidence for the somatic mutation theory of chemical carcinogenesis.